Regulation of expression of transmembrane and soluble 75 kDa tumor necrosis factor receptors by interferon-gamma and granulocyte-macrophage colony-stimulating factor involves transcriptional activation.
The receptors for tumor necrosis factor (TNF) play an important role in the response to this cytokine, both as signal transducing molecules and, in their shed forms, as regulators of TNF availability. Expression of the receptors was studied in the human monocytic leukemia line THP-1. Within two days of incubation, the proinflammatory cytokines, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF), each induced a slight increase in cell surface expression of the 75 kDa TNF receptors (TNF-R75), and a more pronounced increase in the generation of soluble TNF-R75. Similarly, receptor mRNA levels were increased in response to both cytokines. GM-CSF and IFN-gamma in combination induced a much stronger increase in cell surface and soluble receptors as well as in receptor mRNA. Expression of the 55 kDa TNF receptor and its mRNA was largely unaffected by the two cytokines. Experiments using TNF-neutralizing antibodies indicate that the changes in TNF-R75 expression occurred independently of endogenously-produced TNF. The half life of TNF-R75 mRNA in cells exposed to GM-CSF + IFN-gamma did not differ significantly from that in untreated cells. According to nuclear run-on assays the synthesis of TNF-R75 mRNA in cells treated with GM-CSF + IFN-gamma, as well as with the phorbol ester TPA, was markedly increased compared to untreated cells, indicating that the observed changes in receptor expression primarily involve altered transcription of the gene. The results suggest that in inflammatory processes, GM-CSF and IFN-gamma contribute to increased synthesis of TNF-R75 by monocytic cells, a prerequisite for the formation of large amounts of soluble receptors.
Mylius-Spencker
H
H
Institute of Molecular Pharmacology, Medical School Hannover, Germany.
Winzen
R
R
Resch
K
K
Holtmann
H
H
D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008970:Molecular Weight; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000187:drug effects*; D012995:Solubility; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D018124:Receptors, Tumor Necrosis Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor